a) Field of the Invention
The present invention is directed to gonane type and D-homogonane type steroids with a sulfatase-inhibiting and/or estrogenic activity for application in pharmacological research and in the pharmaceutical industry.
b) Description of the Related Art
Steroid-3-sulfamates with a sultamoyloxy group, alkyl group, cycloalkyl group or dialkylsulfamoyloxy group have long been known (DE 3376799, 1968, Schwarz, S., Pharmazie 30 (1975) 17-21). Due to their improved bioavailability and decreased metabolic degradation per hepatic passage, they are used as prodrugs for estrogens in substitution therapy, in the form of combination preparations for contraception, and as substances with scavenging properties.
In steroid sulfamates (DE 2,336,431), only 1,3-dialkylsulfamoyloxy-8xcex1-estratien-17-on as well as certain, possibly substituted, 3,11- and 3,17-disulfamoyloxy estratiens, which are used especially as hormonal contraceptives (WO 96/05216), are identified as likewise having an estrogenic activity. Recently, it was found by M. J. Reed, et al. [Biochemistry 34 (1995) 11508-11514; J. Steroid Biochem. Molec. Biol. 57 (1996) 79-88] that a strong sulfatase-inhibiting activity is exerted by estradiol- and estrone-3-sulfamates. Sulfatase inhibitors can be used to treat estrogen-dependent tumors in that they prevent the release of estradiol or estrone from endogenic steroid conjugates, i.e., the corresponding sulfates. It was subsequently indicated that steroidal sulfatase inhibitors of the estradiol- or estrone-3-sulfamate type can be used only conditionally as sulfatase inhibitors for treating estrogen-dependent tumors. In in vivo experiments, these compounds show an increased estrogenic activity [Elger, W., et al., J. Ster. Biochem. Molec. Biol. 55 (1995) 395-403] which is undesirable in this indication.
Nonsteroidal sulfatase inhibitors with a comparatively high sulfatase-inhibiting activity corresponding to estrone sulfamate have been reported on recently (Li P.-K. et al., J. Ster. Biochem. Molec. Biol. 59 (1996) 41-48).
Complete suppression of estrogenic activity was not previously observed in the nonsteroidal and steroidal sulfatase inhibitors with constant or improved sulfatase-inhibiting activity.
Therefore, there is a need for compounds which limit or prevent the availability of estrogens in hormone-dependent tumors, wherein there is an interest in sulfatase inhibitors having no estrogenic active component.
Further, it is known that the estrogenicity of estradiol can be varied through specific substitution in the D ring. Oral effectiveness can be decisively improved by substitution (alkylation or acetylation) of the proton residing geminal to the 17-hydroxy group. Substitution of the proton vicinal to the 17xcex2-hydroxy group in the 16-position leads to reduced oral effectiveness. Substituting halogen or pseudohalogen leads to so-called braked, i.e., slightly or moderately effective, estrogens.
Further, since liver toxicity has been determined in long-term testing with 17-alkylated or acetylated estradiol derivatives, there is interest in highly effective estrogens with low toxicity in order to detach these compounds.
The object is met by providing new steroid sulfamoyloxy derivatives which are produced by suitable sulfamoylation reactions. It has been found that certain steroidal sulfamoyloxy compounds with more than one sulfamate grouping in the molecule, in particular those that are sulfamoylated at the characteristic positions for estrogenic activity, including substituents or side-chains (e.g., in the 7-position and/or 11-position) which can be found at the periphery of the steroid skeleton, show a clear increase in sulfatase activity with reduced estrogenic activity. In some cases, the estrogenicity can be reduced to such an extent that even antiestrogenic effects are observable.
According to the invention, it was found that compounds of the estradiol disulfamate and 16-halogen-estradiol disulfamate type have a greater sulfatase inhibition than any known compounds and, moreover, do not exhibit any estrogenicity. Due to the halogen substitution in the 16-position, the sulfatase-inhibiting activity is further increased compared with the unsubstituted compound.
Some monosulfamates, with the exception of the A-ring sulfamoyloxy compounds, show significant sulfatase activity with reduced estrogenicity. Synergistic effects are observed in the presence of two or more such pharmacophores in a molecule. In some cases, these effects lead to a multiplying of of the activity in comparison to the standard compounds, which was confirmed with respect to disulfamates and trisulfamates.
Due to the influencing of the estrogen biosynthesis, the direct sulfatase inhibition and other antiestrogenic effects, the availability of estrogens is limited or can be regulated, which can be utilized for the treatment of estrogen-dependent tumors and for diagnostics.
The direction of the pharmacological effect of the sulfamoyloxy compounds can be specifically changed depending on the substitution pattern, which makes it possible to use them as sulfatase inhibitors on the one hand and as estrogen components on the other hand. Surprisingly, in-vitro potential estrogen activities can be detected in some sulfamates by means of an estrogen transcription assay. In this test, 3,17-disulfamoyloxy compounds are found to be inactive.
The 16-substituted 3-monosulfamates which are the subject of this invention show an extraordinary therapeutic breadth. In addition to high sulfatase activity, these compounds are characterized by high estrogenicity. This is surprisingly high compared with the known highly effective estrone- or estradiol-3-sulfamates. According to the prior art, 16-halogen- or pseudohalogen-estradiols are less effective compared with estriol or estradiol. Estrogenicity is considerably increased by introducing the sulfamate group in the 3-position. Accordingly, 16xcex1-bromoestradiol-3-sulfamate applied orally in vivo is five times more effective than estriol and three times more effective than estradiol-3-sulfamate. Based on these findings, new orally effective estrogens are available for contraception and hormone replacement therapy on the one hand and for diagnostics in the application of radioactive species (PET) on the other hand.
In marked form, especially in the case of short-lived isotopes such as [18F], [76Br] or Tc, etc., the compounds according to the invention represent potential markers for diagnosing diseased tissue, including cancerous tissue, due to their target specificity relative to steroid sulfatase as well as estrogen receptors.
The compounds according to the invention are extremely effective sulfatase inhibitors which are suitable, by themselves or in combination with other active components, e.g., aromatase inhibitors or antiestrogens, for the treatment of diseases in relation to inhibition of sulfatases or estrogens, e.g., for treating hormone-dependent tumors.
Further, some of the steroidal sulfamoyloxy compounds in combination with a gestagen are also important means for contraception and for the treatment of climacteric complaints.
The compounds according to the invention having the general formula I, can be used as pharmaceuticals. Production of these preparations is carried out by galenic methods, known per se, by mixing with organic and/or inorganic inert carrier materials suitable for enteral, percutaneous or parenteral applications.
Suitable dosages can be determined routinely by determining bioequivalence relative to a known sulfatase inhibitor or a known estrogen. The dosage of the compounds according to the invention ranges from 0.001 to 200 mg per day.
The sulfamoyloxy compounds according to the invention are steroids of the gonane type and D-homo-gonane type according to formula I, 
wherein there is possibly an additional double bond between C atoms 9 and 11, 8 and 9, 8 and 14, 14 and 15, 15 and 16, 6 and 7, or 7 and 8,
or wherein there are possibly two double bonds between C atoms 8, 9, 14, 15 or 8, 9, 7, 6,
or which contain a cyclopropane grouping or epoxide grouping with xcex1- or xcex2-orientation between C atoms 14 and 15 or 15 and 16,
wherein C atoms 2, 3, 4, 6, 7, 11, 12, 15, 16 and/or 17 are unsubstituted or are substituted by C1-C6-alkyloxy, C1-C4-alkyloxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C6-alkanoyloxy or tris-(C1-C4-alkyl)-silyloxy or hydroxy, wherein a keto grouping xe2x80x94C(xe2x95x90O)xe2x80x94, which is possibly protected in the form of a ketal, thioketal, cyanhydrin, cyanosilyl ether or a geminal hydroxyethinyl group, can also be present instead of a secondary hydroxy group xe2x80x94CH(OH)xe2x80x94,
wherein n=1 or 2,
R1=xcex1-methyl or xcex2-methyl or xcex1-ethyl or xcex2-ethyl for H, the sulfamoyloxy group xe2x80x94OSO2NHR2 preferably resides at C-1,-2,-3,-4,-6,-7,-11,-15, -16 and/or -17 and further also at groups R4 and/or R5,
R2=H, C1-C5-alkyl, C1-C3-alkyl with annelated saturated ring, aryl-C1-C3-alkyl, C1-C5-alkanoyl, C3-C7-cycloalkylcarbonyl,
R3=H, OH or halogen such as chlorine, bromine, [76Br] bromine, iodine [125I]- or [131I]-iodine, astatine, fluorine or [18F] fluorine, pseudohalogen such as N3, CN, SCN or SeCN, or C1-C3-alkyl, C3-C7-cycloalkyl, 1xe2x80x2,1xe2x80x2-cycloalkyl or aryl-C1-C3-alkyl,
R4=H, aryl or C1-C12-alkyl,
R5=H, C1-C12-alkyl or C1-C12-alkylaryl,
R6=H or halogen, such as chlorine, bromine, [76Br] bromine, fluorine, [18F] fluorine or astatine, and
m=1 to 5, preferably 1 to 3,
with the condition that R3 is different than H and OH when m is 1 and the sulfamoyloxy group is bonded to the aromatic A ring,
and salts thereof, particularly pharmaceutically acceptable salts.
In this connection, 1xe2x80x2,1xe2x80x2-cycloalkyl stands for spiro-C3-C6-alkyl or -alkenyl, aryl-C1-C3-alkyl stands, e.g., for phenyl-C1-C3-alkyl such as benzyl or for heteroar-C1-C3-alkyl, wherein heteroaryl stands for the following groups, for example: pyridine, picoline, lutidine, collidine, quinoline, acridine, pyridazine, pyrimidine, pyrazine, triazine, pterine, pyrrole, indole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, thiazole or thiodiazole. In addition to C3-C7-cycloalkyl, saturated annelated rings include hydrogenated heterocyclic rings such as piperidine, piperazine, pyrrolin, pyrolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, imidazoline or imidazolidine. By aryl is meant a heteroaryl substituent in the aforementioned sense or an o-, m- or p-substituted phenyl group (substituents of a phenyl group are, e.g., halogen, C1-C5-alkylthio, C1-C5-alkyloxy, hydroxy, C1-C5-alkyl, hydroxy-C1-C5-alkyl, C1-C5-alkanoyl, CN, amino, mono- or di-C1-C3-alkylamino, nitro or CHO and acetals and oximes having the formula xe2x80x94CH(OR)(ORxe2x80x2) and xe2x80x94CHxe2x95x90NOR thereof, wherein R and Rxe2x80x2 stand for H or C1-C5-alkyl or R and Rxe2x80x2 together stand for C2-C4-alkylene).
Preferably,
R1=xcex1- or xcex2-methyl or xcex1-ethyl or xcex2-ethyl,
n=1 or 2,
R3=H, OH, chlorine, bromine, fluorine, N3, CN, SCN or SeCN,
m=1 to 3,
R2=in the sulfamoyloxy group or groups (xe2x80x94OSO2 NHR2), H and/or C1-C5-alkyl, C1-C5-alkanoyl, or C3-C7-cycloalkylcarbonyl,
R4=H, aryl or C1-C12-alkyl,
R5=H, C1-C12-alkyl or C1-C12-alkylaryl,
R6=H, chlorine, bromine, or fluorine,
wherein a sulfamoyloxy group can preferably be fixed to the aromatic A ring and/or to an aryl group R4 and, further, to C atoms 7, 11, 15, 16, or 17, under the condition that R3 is different than H and OH when m is 1 and the sulfamoyloxy group is bonded to the aromatic A ring,
and salts thereof.
In further preferred compounds of formula I:
R1=xcex2-methyl or xcex2-ethyl,
R3=bromine, [76Br] bromine, fluorine, [18F] fluorine, [125I]- or [131I]-iodine, or astatine
R6=bromine, [76Br] bromine, fluorine, or [18F] fluorine,
m=1 to 2,
and R2, R4, R5 and n have the above-indicated meanings,
wherein one of the sulfamoyloxy groupings is positioned at the aromatic A ring and when m=2 the second sulfamoyloxy group (xe2x80x94OSO2NHR2) is in the 17xcex1- or 17xcex2-position,
and salts thereof.
Another preferred group of compounds according to the invention relates to those of formula 1,
wherein there is possibly an additional double bond between C atoms 9 and 11, 8 and 9, 8 and 14, 14 and 15, 6 and 7, or 7 and 8,
or wherein there are two double bonds between C atoms 8, 9, 14, 15 or 8, 9, 7, 6, or which contain a cyclopropane grouping or epoxide grouping with xcex1-orientation or xcex2-orientation between C atoms 14 and 15,
wherein C atoms 2, 3, 4, 6, 7, 11, 12, 15, 16 and/or 17 are possibly substituted by C1-C6-alkyloxy, C1-C4-alkyloxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C6-alkanoyloxy or tris-(C1-C4-alkyl)silyloxy, hydroxy, wherein a keto grouping which can be protected in the form of a ketal, thioketal, cyanhydrin, cyanosilylether or a geminal hydroxyethinyl group can also be present instead of a secondary hydroxy group,
wherein n=1 or 2,
R1=xcex1-methyl or xcex2-methyl or xcex2-ethyl for H,
R3=H or halogen such as chlorine, bromine, [76Br] bromine, iodine, astatine, fluorine or [18F] fluorine,
the sulfamoyloxy group xe2x80x94OSO2NHR2 preferably resides at C-1,-2,-3-,-4,-6,-7,-11,-15,-16 and/or -17 and further also at groups R4 and/or R5, and
R2=H, C1-C5-alkyl, C1-C3-alkyl with annelated saturated ring or is aryl-C1-C3-alkyl,
R4=aryl or C1-C12-alkyl,
R5=C1-C12-alkyl,
R6=halogen, such as chlorine, bromine, [76Br] bromine, [18F] fluorine, fluorine or astatine,
m=1 to 5, preferably 1 to 3, under the condition that R3 is different than H when, where m=1, the sulfamoyloxy group is bonded to the aromatic A ring, and salts thereof.
The following compounds of the invention are particularly preferred:
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-D-homo-1,3,5(10)-gonatriene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-8xcex1-D-homo-1,3,5(10)-gonatriene,
3,17xcex2-disulfamoyloxy-13xcex2-ethyl-1,3,5(10)-gonatriene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10),7(8)-gonatetraene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10)8,6-gonapentaene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10),8-gonatetraene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10),8,14-gonapentaene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10),8(14)-gonatetraene,
3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10),9(11)-gonatetraene,
3,17xcex2-disulfamoyloxy-13xcex2-ethyl-1,3,5(10),9(11)-gonatetraene,
3,17xcex2-disulfamoyloxy-14xcex2,15xcex2-methylene-13xcex2-methyl-1,3,5(10)8-gonatetraene,
3,17xcex1-disulfamoyloxy-14xcex2,15xcex2-methylene-13xcex2-methyl-1,3,5(10)8-gonatetraene,
3,17xcex2-disulfamoyloxy-14xcex1,15xcex1-methylene-13xcex2-methyl-1,3,5(10)8-gonatetraene,
3,17xcex1-disulfamoyloxy-14xcex1,15xcex1-methylene-13xcex2-methyl-1,3,5(10)8-gonatetraene,
16xcex1-bromo-3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
16xcex1-bromo-3,17xcex2-disulfamoyloxy-13xcex2-ethyl-1,3,5(10)-gonatriene,
16xcex2-bromo-3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
16xcex1-chloro-3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
16xcex1-chloro-3,17xcex2-disulfamoyloxy-13xcex2-ethyl-1,3,5(10)-gonatriene,
16xcex2-chloro-3,17xcex2-disulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
3,17xcex2-disulfamoyloxy-16xcex1-fluoro-13xcex2-methyl-1,3,5(10)-gonatriene,
3,17xcex2-disulfamoyloxy-16xcex1-fluoro-13xcex2-ethyl-1,3,5(10)-gonatriene,
16xcex1-bromo-3-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-17xcex2-ol,
16xcex1-fluoro-3-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-17xcex2-ol,
16xcex1-chloro-3-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-17xcex2-ol,
17xcex2-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-3-ol,
17xcex2,16xcex2-dihydroxy-3-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene-16,17-sulfate,
3-sulfamoyloxy-16,17-(2xe2x80x2,2xe2x80x2-propylenedioxy)-13xcex2-methyl-1,3,5(10)-gonatriene,
3,16xcex1,17xcex2-trisulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
16xcex1-bromo-3-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-17xcex2-on,
16xcex1-bromo-3-sulfamoyloxy-13xcex2-ethyl-1,3,5(10)-gonatrien-17xcex2-on,
3,17xcex1-disulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
17xcex1-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-3-ol,
16xcex1-fluoro-17xcex2-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-3-ol,
16xcex1-bromo-17xcex2-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatrien-3-ol,
17xcex2-sulfamoyloxy-13xcex2-ethyl-1,3,5(10)-gonatrien-3-ol,
3-methoxy-17xcex2-sulfamoyloxy-13xcex2-methyl-1,3,5(10)-gonatriene,
3-methoxy-17xcex2-sulfamoyloxy-13xcex2-ethyl-1,3,5(10)-gonatriene.
The compounds according to the invention are produced, for example, in that, in a manner known per se, steroid alcohols having the following general formula II, 
where the substituents have the aforementioned meanings,
are dissolved or suspended in a suitable solvent,
are partially or quantitatively converted to alcoholates with a base, which is also possibly carried out by phase transfer catalysis,
or are combined with auffer in the form of a tertiary amine, a pyridine base or an anhydrous salt,
and are reacted with amidosulfuric acid chlorides to form the corresponding amidosulfonates optionally, where m=1 to 5, wherein the amidosulfuric acid chlorides can be N-alkylated or N-alkanoylated.
Halogenated carbohydrates such as methylene chloride or chloroform, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether or ether, acetonitrile, DMF, DMSO, benzene, toluene or mixtures thereof are preferably used as solvents.
NaH, CaH2, lithium alkyls, LDA, lithium naphthalide, potassium tert-butylate, KOH or NaOH, possibly combined with a phase transfer salt, are preferably used as bases for conversion into alcoholates.
Triethylamine, 2,6- or 2,4,6-alkylated pyridine bases, anhydrous K2CO3 or Na2CO3, the latter combined, as the case may be, with a phase transfer salt or a crown ether, are preferably used as buffers.
Sulfamoylation is carried out in stages with amidosulfuric acid chlorides such as sulfamoyl chloride, N-alkyl- or N-alkanoyl-amidosulfuric acid chlorides, possibly of different types.
Care is taken during the reaction for optimum mixing, possibly accompanied by cooling, wherein ultrasonic is advantageously applied.